The ?-hemoglobinopathies sickle cell disease and ?-thalassemia are among the most common, and most devastating, genetic diseases worldwide. In countries with developed health care systems, care for affected individuals is extremely expensive;in developing countries most affected individuals receive substandard or no care, and death in childhood is common. It has long been known that enhanced production of (fetal) ?-globin expression can ameliorate or prevent both diseases, as ?-globin substitutes for the defective ?-globin. A safe and effective drug that will accomplish this has long been sought, but it has been difficult to devise effective high-throughput assays. Here we propose to develop an assay that may produce candidate compounds that have activity in reversing ?-globin silencing in adult-stage red blood cells. This is a cell-based assay that relies on a new application of tried methodology developed by the PI;it is capable of screening many thousands of compounds. These compounds may serve as leads to new classes of active molecules, and can be tested for specific activity in experimental systems that reproduce globin switching. This is a pilot study intended to develop and explore the assay, but the initial testing has revealed that it is capable of identifying compounds with previously undescribed epigenetic activity. This study could thus open a new avenue of approach to a stubborn problem, the solution to which could affect millions of lives worldwide. PUBLIC HEALTH RELEVANCE: Sickle cell disease and _-thalassemia are devastating genetic diseases that are extremely common worldwide and increasingly common in the USA;current medical treatment for them is inadequate and expensive. A cheap and effective drug that could reactivate fetal globin expression would have a major impact on worldwide morbidity and mortality from these diseases, and ease a considerable burden on the health care systems of many developing countries. This proposal presents a new method of searching for chemical compounds that might provide such a cheap and effective treatment;thus it has a potential for a broad impact on public health.